ARID1A Has Context-Specific Roles in Hepatocellular Carcinoma

ARID1A is a component of the SWI/SNF chromatin-remodeling complex that frequently harbors loss-of-function mutations in cancer, including approximately 10% to 15% of hepatocellular carcinomas (HCC), suggesting it may play a tumor suppressive role. However, many HCCs overexpress ARID1A, prompting Sun, Wang, and colleagues to investigate potential context-specific functions of ARID1A in liver tumorigenesis. In mouse models of MYC- and chemical-induced HCC initiation, Arid1a loss protected against tumor initiation. Conversely, ARID1A overexpression accelerated HCC tumorigenesis, consistent with a requirement for ARID1A in tumor initiation. Mechanistically, ARID1A loss protected against tumorigenesis by decreasing transcription of the CYP450 superfamily of monooxygenase enzymes, resulting in a decrease in reactive oxygen species (ROS) that protected against liver injury and hepatocarcinogenesis. Immunostaining of 34 human HCC samples revealed that ARID1A staining was elevated in 86% of samples, supporting a role for ARID1A in promoting tumorigenesis. However, in 7 of 21 paired primary and metastatic HCC samples, ARID1A was expressed in the primary tumors but lost in the metastases. Further, ARID1A depletion increased HCC cell migration and invasion in vitro, and Arid1a loss promoted tumor progression and metastasis in established mouse HCC. In established tumors, Arid1a haploinsufficiency resulted in global chromatin remodeling to reduce chromatin accessibility and reduce expression of genes associated with suppression of migration, invasion, and metastasis, thereby enhancing metastasis. These findings support a model in which ARID1A expression is required for maintenance of ROS levels and tumor initiation and subsequent ARID1A loss promotes metastasis, altogether indicating that ARID1A has context-dependent tumor-suppressive and oncogenic roles in HCC.

Sun X, Wang SC, Wei Y, Luo X, Jia Y, Li L, et al. Arid1a has context-dependent oncogenic and tumor suppressor functions in liver cancer. Cancer Cell 2017;32:574–89.

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